A DNA-encoded library for the identification of natural product binders that modulate poly (ADP-ribose) polymerase 1, a validated anti-cancer target
A DNA-encoded library for the identification of natural product binders that modulate poly (ADP-ribose) polymerase 1, a validated anti-cancer target
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DOI：
10.1016/j.bbrc.2020.04.022
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发表时间：
2020-12-03
影响因子：
3.1
通讯作者：
Ma, Peixiang
中科院分区：
文献类型：
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作者：
Li, Jie;Li, Yu;Ma, Peixiang
天然产物一直是药物发现的宝贵来源，但它们的靶点在很大程度上仍然未知。天然产物富集的dna编码化学文库（nDELs）使研究人员能够快速、经济地筛选针对各种蛋白质靶点的众多天然产物，从而促进了分子机制的阐明。在这项工作中，我们以聚（adp -核糖）聚合酶1 （PARP1）为例，探讨了nDEL在功能性天然产物选择中的应用。我们使用后期修饰方法用独特的DNA条形码标记三种阳性结合物，其解离常数范围从亚微摩尔到微摩尔。根据这些对照的丰富性，建立了筛选标准。该标准选择的5种天然产物在SPR中直接与PARP1结合，其中木犀草素对PARP1的抑制活性最高。此外，木犀草素选择性地诱导brca缺陷细胞中DNA双链断裂的积累和G2/M期阻滞。这些研究结果均支持木犀草素抑制PARP1是其抗癌作用的机制之一。(C) 2020由爱思唯尔公司出版。
Natural products have been an invaluable source of drug discovery, but their targets remain largely unknown. Natural products enriched DNA-encoded chemical libraries (nDELs) empower the researchers to rapidly and economically screen numerous natural products against various protein targets, and therefore promote the elucidation of the molecular mechanisms. In this work, we used poly (ADP-ribose) polymerase 1 (PARP1), as an example to explore the usage of nDEL for the functional natural products selection. We used late-stage modification approach to label three positive binders with unique DNA barcodes, whose dissociation constants range from sub-micromolar to micromolar. The selection criterion was set up according to the enrichment of these controls. Five natural products selected by this criterion directly bind to PARP1 in SPR, among which luteolin exhibits the highest inhibitory activity against PARP1. Moreover, luteolin selectively induces accumulation of DNA double-strand breaks and G2/M phase arrest in BRCA-deficient cells. All the findings from these investigations on luteolin support that PARP1 inhibition is one of the mechanisms for its anti-cancer activity. (C) 2020 Published by Elsevier Inc.